Multiple organ failure (MOF) is a major source of morbidity and mortality in patients requiring intensive care. Increasing evidence has suggested that bacteria and toxins of intestinal origin may play an important role in its pathogenesis through a process known as bacterial translocation, in which microorganisms and toxins elaborated by bacteria normally resident within the intestinal lumen cross the bowel wall and invade tissues of the host. A major mechanism by which translocation occurs is through altered permeability of the intestinal mucosa. Interestingly, the administration of nutrients and energy substrates via total parenteral nutrition (TPN), a common event in the intensive care unit (ICU) setting, has been shown experimentally to alter gut mucosal function and enhance bacterial translocation. In fact, the large preponderance of patients developing MOF have an antecedent history of receiving their nutritional needs solely via a parenteral route. It is well known that animals receiving TPN for sustained periods (i.e. one week or longer) have evidence of atrophic changes in the gut mucosa that presumably occur because trophic factors normally released by oral alimentation to keep the epithelium healthy are not present in the parenterally fed state. Thus, it is entirely possible that intestinal mucosal aberrations induced by TPN set the stage for translocation to occur in the ICU patient. Whether the degree of translocation is substantial enough to induce MOF will depend on the existence of other factors that are also known to promote translocation. It is our HYPOTHESIS that when translocation becomes profound enough so that the host cannot prevent it, MOF supervenes. Based on these observations, the present proposal will address three specific aims. The first aim will determine the role of gut mucosal dysfunction in promoting translocation. The TPN treated rat will be used for these studies and its effect on mucosal dysfunction and resultant translocation will be compared with animals receiving their nutritional needs by an enteral route or oral feeding with normal rat chow. Further, aberrations in normal gut function by altering ornithine decarboxylase (ODC) activity or glutathione synthesis and resultant effects on translocation will also be compared with these other models. The second aim will determine the role of other perturbing factors on bacterial translocation when an underlying mucosal dysfunction is present. These studies will utilize models developed under the first specific aim and assess such perturbing factors as morphine, shock, antibiotics, and intraabdominal infection, all factors known to enhance translocation. The third aim will determine the role of reversing mucosal dysfunction in preventing translocation. These studies will assess trophic factors such as gastrin and epidermal growth factor, the antioxidant glutathione, and polyamines which appear to influence mucosal health through their production by ODC. For all studies, hepatic function and histoarchitecture will be evaluated as an index of organ failure associated with translocation.